Cystatin C Shifts APP Processing from Amyloid-? Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells.

ABSTRACT: Amyloid-? (A?), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from sequential proteolytic cleavage of amyloid protein precursor (APP) by secretases. In this study, we found that cystatin C (CysC), a natural cysteine protease inhibitor, is able to reduce A?40 secretion in human brain microvascular endothelial cells (HBMEC). The CysC-induced A?40 reduction was caused by degradation of ?-secretase BACE1 through the ubiquitin/proteasome pathway. In contrast, we found that CysC promoted secretion of soluble APP? indicating the activated non-amyloidogenic processing of APP in HBMEC. Further results revealed that ?-secretase ADAM10, which was transcriptionally upregulated in response to CysC, was required for the CysC-induced sAPP? secretion. Knockdown of SIRT1 abolished CysC-triggered ADAM10 upregulation and sAPP? production. Taken together, our results demonstrated that exogenously applied CysC can direct amyloidogenic APP processing to non-amyloidgenic pathway in brain endothelial cells, mediated by proteasomal degradation of BACE1 and SIRT1-mediated ADAM10 upregulation. Our study unveils previously unrecognized protective role of CysC in APP processing.

SUBMITTER: Wang XF 

PROVIDER: S-EPMC4988779 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature